Pilot Plant Scale Up Considerations for Solids

Scaling up from a pilot plant to full-scale production of solid dosage forms involves several critical considerations to ensure successful outcomes and maintain product quality. First, selecting appropriate equipment is essential; it must be compatible with the properties of the solids, such as particle size and flowability, while also having sufficient capacity for production demands. Process optimization plays a key role, particularly in areas like mixing and granulation, where precise conditions can significantly impact uniformity. The flow characteristics and compressibility of materials need thorough evaluation to ensure consistent performance during tablet production. Additionally, formulation adjustments may be necessary, ensuring excipients are suitable for larger batches and that the formulation remains stable. Quality control measures must be robust, incorporating analytical methods and in-process testing to monitor critical parameters. Regulatory compliance is paramount, requiring detailed documentation and validation studies to demonstrate adherence to quality criteria. Effective risk management strategies should be in place to anticipate challenges that may arise during scale-up. Lastly, a well-trained workforce is crucial to navigate new equipment and processes, ensuring high-quality standards are met throughout the transition. By addressing these factors, pharmaceutical manufacturers can effectively manage the complexities of scaling up solid dosage forms, ultimately delivering safe and effective products.

1. INDUSTRIAL PHARMACY II - DAKSHINESH 1 NANDHA COLLEGE OF PHARMACY ERODE-52 NAME: DAKSHINESH P COURSE: B.PHARM SEMESTER: VII

2. INDUSTRIAL PHARMACY II PILOT PLANT SCALE UP CONSIDERATIONS FOR SOLIDS INDUSTRIAL PHARMACY II - DAKSHINESH 2

3. The following points to be carefully consider during scaling up the solid dosage forms; Batch size from intermediate to large scale production. Each stage of operation. Different types of equipment. Use of sophisticated instruments with larger volume load. Various sizes of equipment. INDUSTRIAL PHARMACY II - DAKSHINESH 3

4. Material Handling: The handling of materials is quite different and necessary to handle carefully in medium and large scale production from the laboratory scale (Mostly poured by hand or scooped). The characteristics of materials like density, size, shape and static charge must be taken into consideration while adopting the processing steps like; Lifting and tilting of drums, Vacuum loading system, Screw feeding systems, Metering pump systems . INDUSTRIAL PHARMACY II - DAKSHINESH 4

5. Any material handling system must deliver the accurate amount of the ingredient to the destination. The cross contamination must be prevented if a system uses transfer of materials for more than one product step. This is accomplished by use of validated cleaning procedure for the equipment. INDUSTRIAL PHARMACY II - DAKSHINESH 5

6. Chemical Weighing: The incorrect ingredients and quantities may lead to cross contamination and misbranded brand during chemical weighing. A central weighing department should have for all the processing areas due to following advantages; Centralization of responsibility, Avoidance of duplicating weighing facility, Lower labor cost. INDUSTRIAL PHARMACY II - DAKSHINESH 6

7. A chemical weighing department should be designed to provide supervision, checkers, lightening, dust collection, adequate sanitation, proper weighing equipment, supply of sink and drain board, cabinets, vacuum supply system, printing scale facility and meters for liquids. For weighing of dye and high potent drugs, a separate room must be equipped. INDUSTRIAL PHARMACY II - DAKSHINESH 7

8. Tablet blending and Granulation: Blending and Granulation: Powders to be used for encapsulation or to be granulated must be well blended to ensure good drug distribution. Inadequate blending at this stage could result in discrete portions of the batch being either high or low in potency to avoid drug content variation. Steps should also be taken to ensure that all the ingredients are free of. INDUSTRIAL PHARMACY II - DAKSHINESH 8

9. The lumps and agglomerates can be removed by doing screening or milling of the ingredients should be done to avoid flow problems, non-reproducible compression and encapsulation process, to facilitate content uniformity of the product. In blending, segregation and mixing operation takes place which depends on particle size, shape, hardness and density. INDUSTRIAL PHARMACY II - DAKSHINESH 9

10. Dry Blending and Direct Compression: Different blenders used in blending are V- blender, double cone blender, Ribbon blender, Slant cone blender, Bin blender, Orbiting screw blenders, vertical and horizontal high intensity mixers. The factors affect the optimization of blending operation of directly compressible materials are; The order of addition of components to the blender. The mixing speed – Planetary type mixer, Tumbling Mixer, Cone Type Mixer. The mixing time –It affects compressibility of Finished Material. INDUSTRIAL PHARMACY II - DAKSHINESH 10

11. The use of auxiliary dispersion equipment with the mixer – Use chopper cell in Twin Shell Mixer. The mixing action – Determined by the Mechanics of the Mixer. The blender loads Optimum working volume and normal working range. INDUSTRIAL PHARMACY II - DAKSHINESH 11

12. Slugging (Dry Granulation): The dry powder cannot be compressed directly due to poor flow and compression properties. The slugging is done by using the Tablet Press of 15 tones. After compression, slugs are broken down by Hammer Mill with suitable particle size distribution. The granulation by dry compaction can also be achieved by passing powders between two roller which put pressure of 10 Tones per linear inch. INDUSTRIAL PHARMACY II - DAKSHINESH 12

13. Wet Granulation: The most common reasons given to justify granulating are; To impart good flow properties to the material, To increase the apparent density of the powders, To change the particle size distribution, Uniform dispersion of active ingredients. Traditionally, wet granulation has been carried out using Sigma blade mixer and Heavy-duty planetary mixer. Wet granulation can also be prepared using tumble blenders equipped with high-speed chopper blades. INDUSTRIAL PHARMACY II - DAKSHINESH 13

14. More recently, the use of multifunctional “processors” that are capable of performing all functions required to prepare a finished granulation, such as dry blending, wet granulation, drying, sizing and lubrication in a continuous process in a single equipment. The factors that affecting the Fluidized Bed Granulator are; Process Inlet Air Temperature, Atomization Air Pressure, Air Volume, Liquid Spray Rate, Nozzle Position and Number of Spray Heads, Product and Exhaust Air Temperature, Filter Porosity. INDUSTRIAL PHARMACY II - DAKSHINESH 14

15. Drying: The most common conventional method of drying a granulation continues to be the circulating hot air oven, which is heated by either steam or electricity. The important factors to consider as part of scale-up of an oven drying operation are airflow, air temperature, and the depth of the granulation on the trays. If the granulation bed is too deep or too dense, the drying process will be inefficient, and if soluble dyes are involved, migration of the dye to the surface of the granules. INDUSTRIAL PHARMACY II - DAKSHINESH 15

16. Drying times at specified temperatures and airflow rates must be established for each product, and for each particular oven load. Fluidized bed dryers are an attractive alternative to the circulating hot air ovens. The important factors considered as part of scale up fluidized bed dryer are optimum loads, rate of airflow, inlet air temperature and humidity. INDUSTRIAL PHARMACY II - DAKSHINESH 16

17. The parameters to be considered for drying process by using Tray Dryer for scale up are Air flow, Air temperature, Depth of the granulation on the trays, Monitoring of the drying process by the use of moisture and temperature probes and Drying times at specified temperatures and air flow rates for each product. The Parameters to be considered for the drying process by using a Fluid Bed Dryer for scale up are Optimum load, Air Flow Rate, Inlet Air Temperature and Humidity of the incoming air. INDUSTRIAL PHARMACY II - DAKSHINESH 17

18. Reduction of Particle size: Compression factors that may be affected by the particle size distribution are flow ability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness, and tablet color uniformity. First step in this process is to determine the particle size distribution of granulation using a series of “stacked” sieves of decreasing mesh openings. INDUSTRIAL PHARMACY II - DAKSHINESH 18

19. Particle size reduction of the dried granulation of production size batches can be carried out by passing all the material through an oscillating granulator, a hammer mill, a mechanical sieving device, or in some cases, a screening device. As part of the scale-up of a milling or sieving operation, the lubricants and glidants, which in the laboratory are usually added directly to the final blend, are usually added to the dried granulation during the sizing operation. This is done because some of these additives, especially magnesium stearate, tend to agglomerate when added in large quantities to the granulation in a blender. INDUSTRIAL PHARMACY II - DAKSHINESH 19

20. Facilities: To avoid cross contamination in scale up and to facilitate the cleaning of equipment effectively, following facilities must be available that are; Presence of separate room with availability of more space, Must have granulation as unit operation, Must have washing and drainage facilities, Must have cold, hot water and steam supply system, Platform should be with stainless steel or non-dust material system, Air condition system is encouraging but if absent, window must be screened, Use of a multifunctional processing system INDUSTRIAL PHARMACY II - DAKSHINESH 20

21. Granulation Handling and Feed System: The handling of the finished granulation in the compression area is either by Hand scooping for small scale or by sophisticated automated handling system with vacuum or mechanical system for large scale. The properties of material like size, size distribution and flow property affects the tablet properties like drug content uniformity, tablet weight, thickness and hardness. For efficient cleaning, sophisticated material handling systems like long lengths transfer tubes, valves, vacuum and pneumatic pumps should be used. INDUSTRIAL PHARMACY II - DAKSHINESH 21

22. Tablet Compression : The tablet press performs following functions during the compression are; Filling of an empty die cavity with granulation. Pre-compression of granulation. Compression of granules. Ejection of the tablet from the die cavity and take-off of the compressed tablet. The prolonged trial runs at press speeds is generally adopted to find out the potential compression problems like sticking to the punch surface, tablet hardness, capping, and weight variation detected. High-speed tablet compression depends on the ability of the press to interact with granulation. INDUSTRIAL PHARMACY II - DAKSHINESH 22

23. During selection of high speed press criteria that should be considered are; Granulation feed rate. Delivery system should not change the particle size distribution. System should not cause segregation of coarse and fine particles. It should induce static charges. The die feed system must be able to fill the die cavities adequately in the short period of time that the die is passing under the feed frame. The smaller the tablet, the more difficult it is to get a uniform to fill high press speeds. INDUSTRIAL PHARMACY II - DAKSHINESH 23

24. For high-speed machines, induced die feed systems with a variety of feed paddles and variable speed capabilities, are necessary. Compression of the granulation usually occurs as a single event as the heads of the punches pass over the lower and under the upper pressure rollers. This causes the punches to penetrate the die to a pre-set depth, compacting the granulation to the thickness of the gap set between the punches. The rapidity and dwell time in between this press event occurs is determined by the speed at which the press is rotating and by the size of compression rollers. INDUSTRIAL PHARMACY II - DAKSHINESH 24

25. Larger the compressions roller, the more gradually compression force is applied and released. Slowing down the press speed or using larger compression rollers can often reduce capping in a formulation. The final event is the ejection of compressed tablets from the die cavity. During compression, the granulation is compacted to form tablet, bonds within compressible material must be formed which results in sticking. High levels of lubricant or over blending can result in a soft tablet, decrease in wet ability of the powder and an extension of the dissolution time. Binding to die walls can also be overcome by designing the die to be 0.001 to 0.005 inch wider at the upper portion than at the centre in order to relieve pressure during ejection. INDUSTRIAL PHARMACY II - DAKSHINESH 25

26. Tablet Coating: Many changes in Sugar coating (Carried in conventional coating pans), due to new developments in coating technology (Conventional sugar coating pan changed to perforated pans or fluidized-bed coating columns), changes in safety and environmental regulations. The development of new polymeric materials has resulted in a change from aqueous sugar coating to aqueous film coating. INDUSTRIAL PHARMACY II - DAKSHINESH 26

27. The tablets must be sufficiently hard to withstand the tumbling to which they are subjected in either the coating pan or the coating column. Some tablet core materials are naturally hydrophobic, and in these cases, film coating with an aqueous system may require special formulation of the tablet core and/or the coating solution. A film coating solution may have been found to work well with a particular tablet in a small lab coating pan but may be totally unacceptable on a production scale. To facilitate the efficient coating the tablet should not be designed as flat surface or Sharpe edges. INDUSTRIAL PHARMACY II - DAKSHINESH 27

28. Encapsulation of Hard Gelatin Capsules: The High Speed equipment is used to prepare the capsule by using the processed powder blend with following particle characteristics like particle size distribution, bulk density, compressibility to promote good flow property. This facilitates the formation of compacts of the right size and of sufficient cohesiveness to be filled into capsule shells. Filling of capsule is done by two filling systems; Zanasi or Martelli form slugs in a dosator . Hofliger-Karg Machine INDUSTRIAL PHARMACY II - DAKSHINESH 28

29. Weight variation in capsules may come due to poor flow characteristics, improper lubrication and plug sticking to the dosator plunger surface. Overlay lubrication may create problems in weight variation, disintegration, dissolution and Bioavailability. The characteristics of granulation and the finished products are greatly influenced by the type and size of equipment used for blending, granulating, drying, sizing and lubrication. INDUSTRIAL PHARMACY II - DAKSHINESH 29

30. For better encapsulation, need of controlled environmental conditions that are Controlled humidity (RH 45 to 55 %) system in processing and encapsulation (RH 35 to 65 %) room and appropriate temperature condition of 15 to 25 °C. INDUSTRIAL PHARMACY II - DAKSHINESH 30

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